Efficacy and safety of the dipeptidyl peptidase‐4 inhibitor gemigliptin compared with sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone

Rhee, Eun-Jung; Lee, Won Young; Min, Kyung Up; Shivane, Vyankatesh; Sosale, Aravind; Jang, Hak Chul; Chung, Choon Hee; Nam-Goong, Il Seong; Kim, J. A.; Kim, S. W.

doi:10.1111/dom.12060

Cited by 43 publications

(62 citation statements)

References 12 publications

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“…25 In a metformin add-on trial performed in 425 Asian patients with inadequately controlled type 2 diabetes being treated with metformin alone, gemigliptin showed comparable efficacy and safety profiles to sitagliptin. 26 In the present study, we observed that the increased urinary excretion of 8-isoprostane after UUO, reflecting the increased oxidative stress in the kidney, was attenuated in mice treated with LC15-0444. However, we did not observe significant differences in plasma 8-isoprostane levels among the four groups.…”

Section: Discussionsupporting

confidence: 52%

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Min

Kim

et al. 2014

Laboratory Investigation

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Dipeptidyl peptidase IV (DPPIV) is an exopeptidase that modulates the function of several substrates, among which insulin-releasing incretin hormones are the most well known. DPPIV also modulate substrates involved in inflammation, cell migration, and cell differentiation. Although DPPIV is highly expressed in proximal renal tubular cells, the role of DPPIV inhibition in renal disease is not fully understood. For this reason, we investigated the effects of LC15-0444, a DPPIV inhibitor, on renal function in a mouse model of renal fibrosis. Eight-week-old C57/BL6 mice were subjected to unilateral ureteral obstruction (UUO) and were treated with LC15-0444 (a DPPIV inhibitor) at a dose of 150 mg/kg per day in food or vehicle for 14 days. DPPIV activity was significantly increased in obstructed kidneys, and reduced after treatment with LC15-0444. Administration of LC15-0444 resulted in a significant decrease in albuminuria, urinary excretion of 8-isoprostane, and renal fibrosis. DPPIV inhibition also substantially decreased the synthesis of several proinflammatory and profibrotic molecules, as well as the infiltration of macrophages. UUO significantly increased, and LC15-0444 markedly suppressed, levels of phosphorylated Smad2/3, TGFb1, toll-like receptor 4, high-mobility group box-1, NADPH oxidase 4, and NF-kB. These results suggest that activation of DPPIV in the kidney has a role in the progression of renal disease and that targeted therapy inhibiting DPPIV may prove to be a useful new approach in the management of progressive renal disease, independent of mechanisms mediated by glucagon-like peptide-1.

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Section: Discussionsupporting

confidence: 52%

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Min

Kim

et al. 2014

Laboratory Investigation

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“…At week 24, both gemigliptin treatments of 50 mg once daily and 25 mg twice daily reduced HbA 1C by 0.81 and 0.77%, respectively, which were non-inferior to 0.80% with 100 mg sitagliptin once daily. 90 The proportion of patients achieving HbA 1C < 7% with gemigliptin 25 mg twice daily (50%) or 50 mg once daily (54%) was comparable to the results with sitagliptin 100 mg once daily (49%). There were significant decreases in FPG and PPG, improvements in glucose tolerance during OGTT, and increases in GLP-1 and b-cell sensitivity to glucose in patients receiving gemigliptin treatment with their metformin therapy.…”

Section: Combination Therapymentioning

confidence: 72%

“…There were significant decreases in FPG and PPG, improvements in glucose tolerance during OGTT, and increases in GLP-1 and b-cell sensitivity to glucose in patients receiving gemigliptin treatment with their metformin therapy. 90 There was no increased risk of adverse effects with gemigliptin compared to sitagliptin 100 mg once daily.…”

Section: Combination Therapymentioning

confidence: 92%

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Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

Chen

Zhou

et al. 2015

Clin Exp Pharma Physio

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SUMMARYDipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycaemic control without causing weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes mellitus (T2DM). The eight available DPP-4 inhibitors, including alogliptin, anagliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with identical mechanism of action and similar safety profiles in patients with T2DM. DPP-4 inhibitors may be used as monotherapy or in double or triple combination with other oral glucoselowering agents such as metformin, thiazolidinediones, or sulfonylureas. Although DPP-4 inhibitors have the same mode of action, they differ by some important pharmacokinetic and pharmacodynamic properties that may be clinically relevant in some patients. The main differences between the eight gliptins include: potency, target selectivity, oral bioavailability, elimination half-life, binding to plasma proteins, metabolic pathways, formation of active metabolite(s), main excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. The off-target inhibition of selective DPP-4 inhibitors is responsible for multiorgan toxicities such as immune dysfunction, impaired healing, and skin reactions. As a drug class, the DPP-4 inhibitors have become accepted in clinical practice due to their excellent tolerability profile, with a low risk of hypoglycaemia, a neutral effect on body weight, and once-daily dosing. It is unknown if DPP-4 inhibitors can prevent disease progression. More clinical studies are needed to validate the optimal regimens of DPP-4 inhibitors for the management of T2DM when their potential toxicities are closely monitored.

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“…For this purpose, we examined whether gemigliptin, a novel DPP-IV inhibitor developed in Korea (Rhee et al, 2013), effectively inhibits NF-κB and JNK mediated activation of inflammatory cascades through modulation of AMPK or Akt phosphorylation and subsequent reduction in the expression of vascular adhesion molecules and inflammatory cytokines in human umbilical vascular endothelial cells (HUVECs). Additionally, we evaluated whether gemigliptin treatment of macrophage-like THP-1 cells significantly reduced foam cell formation via an AMPK or Akt dependent pathway.…”

Section: Introductionmentioning

confidence: 99%

The dipeptidyl peptidase-IV inhibitor inhibits the expression of vascular adhesion molecules and inflammatory cytokines in HUVECs via Akt- and AMPK-dependent mechanisms

Hwang

Chung

Jung

et al. 2015

Molecular and Cellular Endocrinology

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Efficacy and safety of the dipeptidyl peptidase‐4 inhibitor gemigliptin compared with sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone

Abstract: Addition of gemigliptin 50 mg daily to metformin was shown to be efficacious, well tolerated and non-inferior to sitagliptin in patients with type 2 diabetes mellitus.

Cited by 43 publications

References 12 publications

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

The dipeptidyl peptidase-IV inhibitor inhibits the expression of vascular adhesion molecules and inflammatory cytokines in HUVECs via Akt- and AMPK-dependent mechanisms

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